Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2
InChI
InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N
InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: http://adisinsight.springer.com/drugs/800012663Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20657706 | https://www.ncbi.nlm.nih.gov/pubmed/16432198
Curator's Comment: Entinostat (MS-275) is a potent brain region-selective HDAC inhibitor in mice.
https://www.ncbi.nlm.nih.gov/pubmed/16432198
Other study demostartes poor Entinostat (MS-275) brain penetration in non-human primates and rodents.
https://www.ncbi.nlm.nih.gov/pubmed/20657706
No human data reported to date.
Originator
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: # Nihon Schering; Pfizer; University of Tokyo
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
0.3 µM [IC50] | ||
Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
8.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
45.1 ng/mL |
10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
114.3 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508 |
4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
529 ng × h/mL |
10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
586.6 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508 |
4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
51.6 h |
10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
129.7 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508 |
4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin |
ENTINOSTAT plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
18.8% |
10 mg/m² single, oral dose: 10 mg/m² route of administration: Oral experiment type: SINGLE co-administered: |
ENTINOSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/26133921/ |
no | |||
yes [IC50 0.73 uM] | ||||
yes [IC50 9.2 uM] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/21245100/ |
yes | |||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. | 2004 Jan 1 |
|
Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. | 2004 Sep 15 |
|
In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells. | 2005 Jun 15 |
|
Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. | 2006 Aug |
|
The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells. | 2007 Mar |
|
MAGE-A9 mRNA and protein expression in bladder cancer. | 2007 May 15 |
|
Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells. | 2007 Nov |
|
Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues. | 2007 Nov 15 |
|
Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. | 2007 Sep 15 |
|
Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. | 2007 Sep 7 |
|
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. | 2008 Jan 15 |
|
Histone deacetylase inhibitors in lymphoma and solid malignancies. | 2008 Mar |
|
Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts. | 2008 Mar 15 |
|
Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells. | 2008 May |
|
Determination of a benzamide histone deacetylase inhibitor, MS-275, in human plasma by liquid chromatography with mass-spectrometric detection. | 2009 Jan 15 |
|
Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL. | 2009 Jul |
|
Epigenetic modifiers: basic understanding and clinical development. | 2009 Jun 15 |
|
Rescue of major histocompatibility-DR surface expression in retinoblastoma-defective, non-small cell lung carcinoma cells by the MS-275 histone deacetylase inhibitor. | 2009 Mar |
|
Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain. | 2009 May |
|
HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. | 2009 Nov 1 |
|
Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle. | 2009 Sep |
|
Antidepressant actions of histone deacetylase inhibitors. | 2009 Sep 16 |
|
MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells. | 2010 Feb 10 |
|
Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells. | 2010 Nov-Dec |
Patents
Sample Use Guides
Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12839953
Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).
Substance Class |
Chemical
Created
by
admin
on
Edited
Mon Mar 31 18:15:14 GMT 2025
by
admin
on
Mon Mar 31 18:15:14 GMT 2025
|
Record UNII |
1ZNY4FKK9H
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Preferred Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Systematic Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Code | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
EU-Orphan Drug |
EU/3/10/732
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
||
|
NCI_THESAURUS |
C1946
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
209783-80-2
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
4261
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
DB11841
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
ENTINOSTAT
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
100000126009
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
DTXSID0041068
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
C1863
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
442532-99-2
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
SUPERSEDED | |||
|
9016
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
TT-136
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
SUB33300
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
706995
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
CHEMBL27759
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY | |||
|
1ZNY4FKK9H
Created by
admin on Mon Mar 31 18:15:14 GMT 2025 , Edited by admin on Mon Mar 31 18:15:14 GMT 2025
|
PRIMARY |
Related Record | Type | Details | ||
---|---|---|---|---|
|
TARGET->WEAK INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET->WEAK INHIBITOR |
Strongly inhibits HDAC3 in cell-free assays. Phase 3.
INHIBITOR
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Strongly inhibits HDAC1 in cell-free assays. Phase 3.
INHIBITOR
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
Related Record | Type | Details | ||
---|---|---|---|---|
|
ACTIVE MOIETY |
|